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1.
Surg Oncol ; 37: 101549, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33819853

RESUMO

BACKGROUND: The age-dependent survival impact of body mass index (BMI) remains to be fully addressed in patients with gastric carcinoma (GC). We investigated the prognostic impacts of BMI in elderly (≥70 years) and non-elderly patients undergoing surgery for GC. METHODS: In total, 1168 GC patients were retrospectively reviewed. Patients were stratified into 3 groups according to BMI; low (<20), medium (20-25) and high (>25). The effects of BMI on overall survival (OS) and cancer-specific survival (CSS) were assessed using univariate and multivariate Cox hazards models. RESULTS: There were 242 (20.7%), 685 (58.7%) and 241 (20.6%) patients in the low-, medium- and high-BMI groups, respectively. The number of patients with high BMI but decreased muscle mass was extremely small (n = 13, 1.1%). Patients in the low-BMI group exhibited significantly poorer OS than those in the high- and medium-BMI group (P < 0.001). Notably, BMI classification significantly demarcated OS and CSS curves (both P < 0.001) in non-elderly patients, while did not in elderly patients (OS; P = 0.07, CSS; P = 0.54). Furthermore, the survival discriminability by BMI was greater in pStage II/III disease (P = 0.006) than in pStage I disease (P = 0.047). Multivariable analysis focusing on patients with pStage II/III disease showed low BMI to be independently associated with poor OS and CSS only in the non-elderly population. CONCLUSIONS: BMI-based evaluation was useful for predicting survival and oncological outcomes in non-elderly but not in elderly GC patients, especially in those with advanced GC.

2.
BMC Cancer ; 21(1): 338, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33789620

RESUMO

BACKGROUND: The present study aimed to assess the lower invasiveness of robot-assisted transmediastinal radical esophagectomy by prospectively comparing this procedure with transthoracic esophagectomy in terms of perioperative outcomes, serum cytokine levels, and respiratory function after surgery for esophageal cancer. METHODS: Patients who underwent a robot-assisted transmediastinal esophagectomy or transthoracic esophagectomy between April 2015 and March 2017 were included. The perioperative outcomes, preoperative and postoperative serum IL-6, IL-8, and IL-10 levels, and respiratory function measured preoperatively and at 6 months postoperatively were compared in patients with a robot-assisted transmediastinal esophagectomy and those with a transthoracic esophagectomy. RESULTS: Sixty patients with esophageal cancer were enrolled. The transmediastinal esophagectomy group had a significantly lower incidence of postoperative pneumonia (p = 0.002) and a significantly shorter postoperative hospital stay (p < 0.0002). The serum IL-6 levels on postoperative days 1, 3, 5, and 7 were significantly lower in the transmediastinal esophagectomy group (p = 0.005, 0.0007, 0.022, 0.020, respectively). In the latter group, the serum IL-8 level was significantly lower immediately after surgery and on postoperative day 1 (p = 0.003, 0.001, respectively) while the serum IL-10 level was significantly lower immediately after surgery (p = 0.041). The reduction in vital capacity, percent vital capacity, forced vital capacity, and forced expiratory volume at 1.0 s 6 months after surgery was significantly greater in the transthoracic esophagectomy group (p < 0.0001 for all four measurements). CONCLUSIONS: Although further, large-scale studies are needed to confirm our findings, robot-assisted transmediastinal esophagectomy may confer short-term benefits in radical surgery for esophageal cancer. TRIAL REGISTRATION: This trial was registered in the UMIN Clinical Trial Registry ( UMIN000017565 14/05/2015).

3.
J Gastrointest Surg ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33825122

RESUMO

BACKGROUND: Gastroduodenal ulcer perforation is a common abdominal emergency that may be curable without surgical repair in non-elderly patients with localized and stable symptoms. However, the outcomes of nonoperative approaches have rarely been described. METHODS: Using a Japanese national inpatient database, we identified 14,918 patients with gastroduodenal ulcer perforation who were hospitalized and received nonoperative treatment from July 2010 to March 2017. We categorized these patients into three groups according to age: 18 to 64 years (young group, n=8407), 65 to 74 years (old group, n=2616), and ≥75 years (old-old group, n=3895). We investigated the characteristics, treatments, and outcomes in each group. RESULTS: Most of the patients were men (71%), and the median patient age was 62 years (interquartile range, 47-75 years). The old and old-old groups had more comorbidities than the young group. Whereas most patients were administered proton pump inhibitors and various antibiotics (96% and 90%, respectively), only 58% of patients underwent gastric tube placement. Surgical repair >3 days after admission was performed in 7.1% of all patients (6.3% vs. 7.9% vs. 5.5%, P<0.001). The old and old-old groups showed higher mortality (1.4% vs. 8.3% vs. 18%, P<0.001) and morbidity (6.6% vs. 15% vs. 17%, P<0.001) than the young group. The median length of stay was almost 2 weeks (13 vs. 17 vs. 20 days, P<0.001). DISCUSSION: Unlike previous studies, many patients aged >65 years received nonoperative treatment in this nationwide cohort. Our findings provide useful information for clinicians and patients hospitalized for gastric ulcer perforation.

4.
Cytotherapy ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33781711

RESUMO

BACKGROUND AIMS: After therapy with platinum, 5-fluorouracil and taxane, no further recommended therapy is available for recurrent or metastatic esophageal cancer (r/mEC). Here the authors report two phase 1 trials of adoptive γδT-cell therapy, one for treatment-refractory r/mEC (γδT-monotherapy-P1, UMIN000001419) and the other for r/mEC with no prior systemic therapy (DCF-γδT-P1, UMIN000008097). METHODS: For γδT-monotherapy-P1, patients received four weekly and four biweekly injections of autologous γδT cells. For DCF-γδT-P1, patients received docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy consisting of docetaxel (60 mg/m2) and cisplatin (60 mg/m2) on day 1 and continuous injection of 5-fluorouracil (600 mg/m2/day) on days 1-5 of each 28-day cycle; additionally, they received autologous γδT-cell injections on day 15 and day 22 of each cycle. RESULTS: Twenty-six patients were enrolled for γδT-monotherapy-P1. No severe adverse events were associated with γδT-cell therapy. Median overall survival was 5.7 months (95% confidence interval [CI], 4.3-10.0), and median progression-free survival was 2.4 months (95% CI, 1.7-2.8). Eighteen patients received DCF-γδT-P1. All treatment-related adverse events were associated with DCF chemotherapy, not γδT injection. Median overall survival was 13.4 months (95% CI, 6.7-not reached), and median progression-free survival was 4.0 months (95% CI, 2.5-5.7). The response rate and disease control rate were 39% and 78%, respectively. CONCLUSIONS: The use of γδT-cell immunotherapy with or without chemotherapy was safe and feasible for r/mEC patients. Although the authors failed to demonstrate any clinical benefit of γδT-monotherapy-P1, survival benefits were observed in the DCF-γδT-P1 trial.

5.
PLoS One ; 16(3): e0247711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661990

RESUMO

PCR methods are presently the standard for the diagnosis of Coronavirus disease 2019 (COVID-19), but additional methodologies are needed to complement PCR methods, which have some limitations. Here, we validated and investigated the usefulness of measuring serum antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using the iFlash3000 CLIA analyzer. We measured IgM and IgG titers against SARS-CoV-2 in sera collected from 26 PCR-positive COVID-19 patients, 53 COVID-19-suspected but PCR-negative patients, and 20 and 100 randomly selected non-COVID-19 patients who visited our hospital in 2020 and 2017, respectively. The repeatability and within-laboratory precision were obviously good in validations, following to the CLSI document EP15-A3. Linearity was also considered good between 0.6 AU/mL and 112.7 AU/mL for SARS-CoV-2 IgM and between 3.2 AU/mL and 55.3 AU/mL for SARS-CoV-2 IgG, while the linearity curves plateaued above the upper measurement range. We also confirmed that the seroconversion and no-antibody titers were over the cutoff values in all 100 serum samples collected in 2017. These results indicate that this measurement system successfully detects SARS-CoV-2 IgM/IgG. We observed four false-positive cases in the IgM assay and no false-positive cases in the IgG assay when 111 serum samples known to contain autoantibodies were evaluated. The concordance rates of the antibody test with the PCR test were 98.1% for SARS-CoV-2 IgM and 100% for IgG among PCR-negative cases and 30.8% for SARS-CoV-2 IgM and 73.1% for SARS-CoV-2 IgG among PCR-positive cases. In conclusion, the performance of this new automated method for detecting antibody against both N and S proteins of SARS-CoV-2 is sufficient for use in laboratory testing.


Assuntos
Anticorpos Antivirais/sangue , /diagnóstico , Imunoglobulina G/sangue , Imunoglobulina M/sangue , /isolamento & purificação , Anticorpos Antivirais/imunologia , /epidemiologia , /imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Japão/epidemiologia , Medições Luminescentes/métodos , Fosfoproteínas/imunologia , Fosfoproteínas/isolamento & purificação , Sensibilidade e Especificidade , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/isolamento & purificação
6.
Surg Today ; 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33660105

RESUMO

PURPOSE: This study compared the quality of healthcare before and after implementation of a policy restructuring the healthcare delivery system and estimated the impact of centralization. METHODS: We used the National Clinical Database to study patients undergoing esophagectomies from 2011 to 2016. We compared the effect of centralization based on the patient background, surgical mortality, and year of surgery. Difference-in-difference methods based on the generalized estimating equation logistic regression model were used for before-and-after comparisons after adjusting for patient-level expected surgical mortality. RESULTS: In total, 34,640 cases were identified. More cases with risk factors were noted in ultra-low-volume hospitals, where 38.4% of cases in underpopulated areas were treated, than in higher volume facilities, and the operative mortality, readmission within 30 days and length of stay were worse among patients treated in these hospitals. In centralized prefectures, the number of cases per hospital increased over time (7.2 in 2011 to 9.5 in 2016) while the crude operative mortality tended to decrease (3.4% in 2011 to 1.8% in 2016). The difference-in-difference estimator was 0.856 (95% confidence interval: 0.639-1.147, p = 0.298). CONCLUSION: The centralization of ultra-low-volume hospitals did not lead to a deterioration in the quality of care but rather an improving trend.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33609319

RESUMO

BACKGROUND: The high operative mortality rate after hepatopancreatoduodenectomy (HPD) is still a major issue. The present study explored why operative mortality differs significantly due to hospital volume. METHOD: Surgical case data were extracted from the National Clinical Database (NCD) in Japan from 2011 to 2014. Surgical procedures were categorized as major (≥2 sections) and minor (<2 sections) hepatectomy. Hospitals were categorized according to the certification system by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) based on the number of major hepato-biliary-pancreatic surgeries performed per year. The FTR rate was defined as death in a patient with at least one postoperative complication. RESULTS: A total of 422 patients who underwent HPD were analyzed. The operative mortality rates in board-certified A training institutions, board-certified B training institutions, and non-certified institution were 7.2%, 11.6%, and 21.4%, respectively. Multiple logistic regression showed that certified A institutions, major hepatectomy, and blood transfusion were the predictors of operative mortality. Failure to rescue rates were lowest in certified A institutions (9.3%, 17.0%, and 33.3% in certified A, certified B, and non-certified, respectively). CONCLUSIONS: To reduce operative mortality after HPD, further centralization of this procedure is desirable. Future studies should clarify specific ways to improve the failure-to-rescue rates in certified institutions.

8.
Surgery ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33632543

RESUMO

BACKGROUND: Little is known about the survival outcomes of and predictive factors for survival in hemodialysis patients undergoing surgery for gastric cancer. METHODS: We performed a multicenter retrospective study from 9 institutions to investigate the survival outcomes of 75 hemodialysis patients with gastric cancer. Patient characteristics included demographic data, hemodialysis- and gastric cancer-related variables. Multivariate Cox hazards models were applied to determine independent predictors of poor overall survival and non-gastric cancer related death. RESULTS: Stage I disease was predominant (58.7%) in our series. The overall morbidity and the 30-day mortality rates were 25.3% and 1.3%, respectively. The 5-year overall survival rates of patients with pStages I, II, III, and IV disease were 59.2%, 42.9%, 32.3%, and 0%, respectively. Eleven (14.7%) patients died of gastric cancer, whereas many more (40.0%) died owing to causes other than gastric cancer. Non-gastric cancer-related death was especially prevalent in patients with pStages I (95.2%) and II (75.0%) disease. Multivariable analysis revealed advanced age, long duration of hemodialysis (> 5 years), total gastrectomy, and pStage IV disease to be independently associated with poor overall survival. Notably, advanced age, long duration of hemodialysis, and the presence of cardiovascular disease were all independent predictors of non-gastric cancer-related death. Patients with all 3 factors had very poor survival outcomes (3-year overall survival; 14.3%). CONCLUSION: The survival outcomes of hemodialysis patients with gastric cancer, especially those with early-stage gastric cancer, were clearly poor, largely owing to the increased risk of non-gastric cancer-related death. Preoperative comorbidities and hemodialytic features were useful for predicting long-term outcomes of this vulnerable population.

9.
J Hum Genet ; 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33640902

RESUMO

Aberrant DNA methylation in the BRCA1 promoter region causes epigenetic silencing of BRCA1 gene expression, which is critical for breast cancer development. However, how BRCA1 promoter methylation status alters histological features remains poorly understood. Here, we investigated the possibility to predict BRCA1 promoter methylation status based on the morphological and immunohistochemical features of triple-negative breast cancers (TNBCs). The morphological features of 53 TNBCs were evaluated with hematoxylin-eosin staining, with immunohistochemical staining of BRCA1, androgen receptor, p53, cytokeratin 5/6, and epidermal growth factor receptor. BRCA1 promoter methylation status was used to distinguish BRCA1 promoter-methylated tumors (BPMTs) from BRCA1 promoter-unmethylated tumors (BPUTs) dependent on pathological characteristics. BPMTs comprised approximately 26% of the TNBCs. Immunohistochemical analysis found that BRCA1 protein expression was significantly lower in BPMT compared with BPUT (p = 0.016). Morphologically, BPMTs were associated with high mitotic index (p = 0.017), pushing margin (p = 0.017), a circumscribed growth pattern (p = 0.014), and a syncytial growth pattern (p = 0.034) compared with BPUTs. We then assessed the potential of predicting BRCA1 promoter methylation status by using published score systems based on these morphological characteristics. A receiver operating characteristic analysis showed an area under the curve of 0.80. This study found that BRCA1 promoter methylation status could be derived from morphological features and lower BRCA1 expression of TNBCs, which may help identify suitable cases for target treatment with PARP inhibitors.

10.
Sci Rep ; 11(1): 2776, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531605

RESUMO

The accurate and prompt diagnosis of SARS-CoV-2 infection is required for the control and treatment of the coronavirus infection disease 2019 (COVID-19). In this study, we aimed to investigate the time courses of the anti-severe acute corona respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and IgG titers and to evaluate the sensitivity and specificity of such tests according to the specific day after the onset of COVID-19 among a patient population in Japan. We measured the titers of SARS-CoV-2 IgM and IgG in sera from 105 subjects, including 26 symptomatic COVID-19 patients, using chemiluminescent immunoassay (CLIA) methods utilizing magnetic beads coated with SARS-CoV-2 nucleocapsid protein and spike protein. The results of a ROC analysis suggested the possibility that the cutoff values in Japan might be lower than the manufacturer's reported cutoff (10 AU/mL): 1  AU/mL for IgM and 5  AU/mL for IgG. The sensitivity of the test before Day 8 after symptom onset was less than 50%; at Days 9-10, however, we obtained a much higher sensitivity of 81.8% for both IgM and IgG. At 15 days or later after symptom onset, the SARS-CoV-2 IgG test had a sensitivity of 100%. These results suggest that if the number of days since disease onset is taken into consideration, these antibody tests could be very useful for the diagnosis of COVID-19 and similar diseases.


Assuntos
Especificidade de Anticorpos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , /imunologia , /virologia , Ensaio de Imunoadsorção Enzimática , Humanos , Japão
11.
Esophagus ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33625649

RESUMO

BACKGROUND: Chemoradiotherapy is an alternative to surgery for esophageal cancer, with a putatively equivalent outcome. However, disease recurrence after a complete response is common and if follow-up surveillance detects recurrence, salvage treatments for potentially curable disease must follow. METHODS: We conducted a nation-wide questionnaire survey of institutions in Japan certified by the Japanese Esophageal Society to investigate outcomes of primary thoracic esophageal cancer patients initially treated by chemoradiotherapy with complete response diagnoses. The primary endpoint was overall survival, the secondary endpoint disease recurrence. Outcomes of patients who had undergone salvage treatments were also investigated. Cases were excluded from analysis if endoscopic study, endoscopic biopsy, or computed tomography data were lacking. RESULTS: At 41 institutes 544 case records were collected; valid data on 392 patients were obtained; 5-year survival was 74.8%, 5-year disease-free survival, 66.8%. Clinical staging before treatment significantly affected both overall and disease-free survival rates, but differences between adjoining stages were unexpectedly small. The primary relapse site was classified as primary site (n = 58), regional lymph nodes (n = 36), or distant disease (n = 34). Salvage treatments with curative intent (surgery, endoscopic treatments, and additional radiation) were performed on 38, 23, and 4 cases; 5-year survival after esophagectomy (n = 22), endoscopic treatment (n = 23), and lymphadenectomy (n = 9) was 47.4%, 70.9%, and 33.3%, respectively. CONCLUSIONS: A quarter of patients developed recurrent disease, mostly locoregional, after complete response. Complete response patients with originally advanced stage disease had fair clinical outcomes; salvage treatments after locoregional recurrence achieved modest long-term survival.

12.
Breast Cancer Res Treat ; 186(3): 731-739, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33398479

RESUMO

PURPOSE: Although long-term survival is similar between men and women, little is known about the short-term outcomes following breast cancer surgery in men. This study was performed to compare postoperative outcomes adjusted for background factors between men and women with breast cancer using a Japanese nationwide inpatient database. METHODS: This study included 2126 men and 363,468 women who underwent surgery for stage 0-III breast cancer from July 2010 to March 2017. We generated a 1:4 matched-pair cohort matched for age, institution, and fiscal year at admission. We then conducted multivariable regression analyses to compare postoperative complications, 30-day readmission, duration of anesthesia, length of hospitalization, and total hospitalization costs between the sexes. RESULTS: Men were older, more likely to have comorbidities and advanced cancer, and more likely to undergo total mastectomy and axillary dissection than women. There were no significant differences in postoperative complications between the sexes, but men showed a lower risk of 30-day readmission (odds ratio 0.74; 95% confidence interval [CI] 0.57-0.95), shorter duration of anesthesia (difference - 22.0 min; 95% CI - 2.1 to - 0.5), shorter length of hospitalization (difference - 1.3 days; 95% CI - 2.1 to - 0.5), and lower total hospitalization costs (difference - 506 US dollars; 95% CI - 668 to - 334) than women. CONCLUSIONS: The matched-pair cohort analyses revealed no significant differences in postoperative complications between men and women with breast cancer. However, men showed better outcomes than women in terms of 30-day readmission, duration of anesthesia, length of hospitalization, and total hospitalization costs.

13.
J Infect Chemother ; 27(5): 690-695, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33349571

RESUMO

INTRODUCTION: Some clinicians administer antibiotics in adhesive SBO treatment to prevent bacterial translocation without evidence confirming reduced sepsis and mortality. We aimed to evaluate the effectiveness of preventive antibiotic administration in nonoperative treatment of adhesive small bowel obstruction (SBO) in a retrospective study. METHODS: Using a Japanese national inpatient database, we identified 114,786 eligible patients with adhesive SBO and divided patients into a group who did not receive intravenous antibiotics in the initial 2 consecutive days after admission (control group, n = 71,666) and a group who received intravenous antibiotics ≥2 days after admission (antibiotic group, n = 43,120). To compare the in-hospital mortality, occurrence of sepsis, septic shock, Clostridioides difficile colitis, length of stay, and total costs between the two groups, we performed instrumental variable analyses to adjust for measured and unmeasured confounding factors. RESULTS: Overall, in-hospital mortality was 2.2%, and the occurrence of sepsis was 0.8%. In the instrumental variable analyses, no significant differences were found for in-hospital mortality, occurrence of sepsis, septic shock, Clostridioides difficile colitis, or total hospitalization costs. The antibiotic group showed a longer length of stay than the control group (coefficient, 1.9 days; 95% confidence interval, 0.6-3.2). CONCLUSIONS: In this large nationwide cohort of patients with adhesive SBO, we found no benefit regarding preventive antibiotic administration in nonoperative treatment; however, antibiotic administration was associated with a longer hospital stay. These results did not support routine administration of antibiotics at admission to prevent bacterial translocation.

14.
Carcinogenesis ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33284950

RESUMO

Cancer-associated fibroblasts (CAFs) tend to have tumor-promoting capacity, and can provide therapeutic targets. Even without cancer cells, CAF phenotypes are stably maintained, and DNA methylation and H3K27me3 changes have been shown to be involved. Here, we searched for a potential therapeutic target in primary CAFs from gastric cancer and a mechanism for its dysregulation. Expression microarray using eight CAFs and seven non-CAFs (NCAFs) revealed that serum amyloid A1 (SAA1), which encodes an acute phase secreted protein, was second most upregulated in CAFs, following IGF2. Conditioned medium (CM) derived from SAA1-overexpressing NCAFs was shown to increase migration of gastric cancer cells compared to that from control NCAFs, and its tumor-promoting effect was comparable to that of CM from CAFs. In addition, increased migration of cancer cells by CM from CAFs was mostly canceled with CM from CAFs with SAA1 knockdown. Chromatin immunoprecipitation (ChIP)-quantitative PCR showed that CAFs had higher levels of H3K27ac, an active enhancer mark, in the promoter and the two far upstream regions of SAA1 than NCAFs. Also, BET bromodomain inhibitors, JQ1 and mivebresib, decreased SAA1 expression and tumor-promoting effects in CAFs, suggesting SAA1 upregulation by enhancer activation in CAFs. Our present data showed that SAA1 is a candidate therapeutic target from gastric CAFs and indicated that increased enhancer acetylation is important for its overexpression.

15.
Dis Esophagus ; 33(Supplement_2)2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33241301

RESUMO

Pulmonary complications, and especially pneumonia, remain one of the most common complications after esophagectomy for esophageal cancer. These complications are reduced by minimally invasive techniques or by avoiding thoracic access through a transhiatal approach. However, a transhiatal approach does not allow for a full mediastinal lymphadenectomy. A transcervical mediastinal esophagectomy avoids thoracic access, which may contribute to a decrease in pulmonary complications after esophagectomy. In addition, this technique allows for a full mediastinal lymphadenectomy. A number of pioneering studies have been published on this topic. Here, the initial experience is presented as well as a review of the current literature concerning transcervical esophagectomy, with a focus on the robot-assisted cervical esophagectomy procedure.

16.
Microorganisms ; 8(11)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198173

RESUMO

The Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is characterized by the infiltration of lymphocytes and a unique tumor microenvironment. Exosomes from cancer cells are essential for intercellular communication. The aims of this study were to investigate the secretion of EBVaGC exosomes and their physiological effect on dendritic cell maturation in vitro and to characterize dendritic cells (DCs) in EBVaGC in vivo. Western blotting analysis of CD63 and CD81 of exosomes from EBV-infected gastric cancer cell lines indicated an increase in exosome secretion. The fraction of monocyte-derived DCs positive for the maturation marker CD86 was significantly suppressed when incubated with exosomes from EBV-infected gastric cancer cell lines. Immunohistochemical analysis of GC tissues expressing DC markers (S100, Langerin, CD1a, CD83, CD86, and BDCA-2) indicated that the density of DCs was generally higher in EBVaGC than in EBV-negative GC, although the numbers of CD83- and CD86-positive DCs were decreased in the group with high numbers of CD1a-positive DCs. A low number of CD83-positive DCs was marginally correlated with worse prognosis of EBVaGC in patients. EBVaGC is a tumor with abundant DCs, including immature and mature DCs. Moreover, the maturation of DCs is suppressed by exosomes from EBV-infected epithelial cells.

17.
Clin Transl Immunology ; 9(10): e1194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101677

RESUMO

Objectives: A better understanding of antitumor immunity will help predict the prognosis of gastric cancer patients and tailor the appropriate therapies in each patient. Therefore, we propose a novel immunological classification of gastric cancer. Methods: We performed whole-exome sequencing (WES), RNA-Seq and flow cytometry in 29 gastric cancer patients who received surgery. The TCGA data set of 323 gastric cancer patients and RNA-Seq data of 45 patients who received pembrolizumab (Kim et al. Nat Med 2018; 24: 1449-1458) were also analysed. Results: Immunogram analysis of cancer-immunity interaction of gastric cancer revealed immune signatures of four main types, designated Hot1, Hot2, Intermediate and Cold. Immunologically hot tumors displayed a dysfunctional T-cell signature, while cold tumors had an exclusion signature. Ex vivo tumor-infiltrating lymphocyte analysis documented T-cell dysfunction with the expression of checkpoint molecules and impaired cytokine production. The T-cell function was more profoundly damaged in Hot1 than Hot2 tumors. Patients in Hot2 subtypes had better survival in our cohort and TCGA cohort. Although these immunological subtypes overlapped to some degree with the molecular subtypes in the TCGA, intratumoral immune responses cannot be predicted solely based on histological or molecular subtyping of gastric cancer. Molecular and immunological classifications complement each other to predict the responses to anti-PD-1 therapy and have the potential to be a biomarker for the treatment of gastric cancer. Conclusion: The immunological classification of gastric cancer resulted in four subtypes. Hot tumors were further divided into two subtypes, between which the functional status of T cells was different.

18.
Gastric Cancer ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037492

RESUMO

BACKGROUND: Despite interest in surgeon and hospital volume effects on total gastrectomy (TG), clinical significance has not been confirmed in a large-scale population. This study aimed at clarifying the association of surgeon and hospital volume on postoperative mortality after TG for gastric cancer among Japanese patients in National Clinical Database (NCD). METHODS: Between 2011 and 2015, we retrospectively extracted data on TG for gastric cancer from the NCD. The primary outcome was operative mortality. We divided surgeon volume as the number of TGs performed by a patient's surgeon in the previous year: S1 (0-2 cases), S2 (3-9), S3 (10-25), S4 (26-79) and hospital volume by the number of TGs performed in the previous year: H1 (0-11 cases), H2 (12-26), H3 (27-146). We calculated the 95% confidence interval (CI) for the mortality rate based on odds ratios (OR) estimated from a hierarchical logistic regression model. RESULTS: We analyzed 71,307 patients at 2051 institutions. Low-volume surgeons and hospitals had significantly older and poorer-risk patients with various comorbidities. The operative mortality rate decreased with surgeon volume, 2.5% in S1 and 0.6% in S4. The operative mortality was 3.1% in H1, 1.7% in H2, and 1.2% in H3. After risk adjustment for surgeon, hospital volume and patient characteristics, hospital volume was significantly associated with operative morality (H3: OR = 0.53, 95% CI 0.43-0.63). CONCLUSIONS: We demonstrate hospital volume has an impact on postoperative mortality after TG in a nationwide population study. These findings suggest centralization may improve outcomes after TG.

19.
Br J Cancer ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33046803

RESUMO

BACKGROUND: Breast fibroadenoma (FA) and phyllodes tumour (PT) often have variations of gene mediator complex subunit 12 (MED12) and mutations in the telomerase reverse transcriptase promoter region (TERTp). TERTp mutation is usually tested by Sanger sequencing. In this study, we compared Sanger sequencing and droplet-digital PCR (ddPCR) to measure TERTp mutations in FA and PT samples. METHODS: FA and PT samples were collected from 82 patients who underwent surgery at our institution from 2005 to 2016. MED12 mutations for all cases and TERTp mutations for 17 tumours were detected by Sanger sequencing. ddPCR was performed to analyse TERTp mutation in all cases. RESULTS: A total of 75 samples were eligible for analysis. Sanger sequencing detected MED12 mutations in 19/44 FA (42%) and 21/31 PT (68%). Among 17 Sanger sequencing-tested samples, 2/17 (12%) were TERTp mutation-positive. In ddPCR analyses, a significantly greater percentage of PT (19/31, 61%) was TERTp mutation-positive than was FA (13/44, 30%; P = 0.0046). The mutation positivity of TERTp and MED12 did not correlate, in either FA or PT. CONCLUSIONS: ddPCR was more sensitive for detecting TERTp mutation than Sanger sequencing, being able to elucidate tumorigenesis in FA and PT.

20.
Ann Surg ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33065635

RESUMO

OBJECTIVES: To investigate the effect of geriatric variables on five newly added outcomes and create risk models for predicting these outcomes. SUMMARY BACKGROUND DATA: Because there is a current lack of geriatric research focusing on geriatric outcomes using a national surgical database in Japan, there is a need to investigate outcomes associated with major gastroenterological surgery using these data. METHODS: This multicenter prospective cohort study was conducted at 26 surgery departments across 21 institutions in Japan using the National Clinical Database (NCD) surgical registry. In total, 22 new geriatric variables were imported from the ACS NSQIP geriatric pilot study. The following five geriatric outcomes were defined: 1) postoperative delirium, 2) physical function on postoperative day 30, 3) fall risk on discharge, 4) discharge other than home with social service, and 5) functional decline on discharge, and geriatric risk prediction models for major gastroenterological surgery were created. RESULTS: Between January 2018 and December 2018, data on 3,981 procedures from seven major gastroenterological surgeries were collected and analyzed. Older age and preoperative geriatric variables (Origin status from home, History of dementia, Use of mobility aid, Fall history, and Not competent on admission) were strongly associated with postoperative outcomes. Geriatric risk prediction models for these outcomes were created, with C-statistic values ranging from 0.74 to 0.90, demonstrating model validity and sufficiency of fit. CONCLUSIONS: The risk models for the newly defined five geriatric outcomes that we created can be used in the decision-making process or provision of care in geriatric patients.

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